Comparative effectiveness and cost-effectiveness of natalizumab and fingolimod in rapidly evolving severe relapsing-remitting multiple sclerosis in the United Kingdom.

AIM: To evaluate the real-world comparative effectiveness and the cost-effectiveness, from a UK National Health Service perspective, of natalizumab versus fingolimod in patients with rapidly evolving severe relapsing-remitting multiple sclerosis (RES-RRMS). METHODS: Real-world data from the MSBase Registry were obtained for patients with RES-RRMS who were previously either naive to disease-modifying therapies or had been treated with interferon-based therapies, glatiramer acetate, dimethyl fumarate, or teriflunomide (collectively known as BRACETD). Matched cohorts were selected by 3-way multinomial propensity score matching, and the annualized relapse rate (ARR) and 6-month-confirmed disability worsening (CDW6M) and improvement (CDI6M) were compared between treatment groups. Comparative effectiveness results were used in a cost-effectiveness model comparing natalizumab and fingolimod, using an established Markov structure over a lifetime horizon with health states based on the Expanded Disability Status Scale. Additional model data sources included the UK MS Survey 2015, published literature, and publicly available sources. RESULTS: In the comparative effectiveness analysis, we found a significantly lower ARR for patients starting natalizumab compared with fingolimod (rate ratio [RR] = 0.65; 95% confidence interval [CI], 0.57-0.73) or BRACETD (RR = 0.46; 95% CI, 0.42-0.53). Similarly, CDI6M was higher for patients starting natalizumab compared with fingolimod (hazard ratio [HR] = 1.25; 95% CI, 1.01-1.55) and BRACETD (HR = 1.46; 95% CI, 1.16-1.85). In patients starting fingolimod, we found a lower ARR (RR = 0.72; 95% CI, 0.65-0.80) compared with starting BRACETD, but no difference in CDI6M (HR = 1.17; 95% CI, 0.91-1.50). Differences in CDW6M were not found between the treatment groups. In the base-case cost-effectiveness analysis, natalizumab dominated fingolimod (0.302 higher quality-adjusted life-years [QALYs] and £17,141 lower predicted lifetime costs). Similar cost-effectiveness results were observed across sensitivity analyses. CONCLUSIONS: This MSBase Registry analysis suggests that natalizumab improves clinical outcomes when compared with fingolimod, which translates to higher QALYs and lower costs in UK patients with RES-RRMS.

There are several medications used to treat people with relapsing remitting multiple sclerosis, such as interferon-based therapies (Betaferon/Betaseron (US), Rebif, Avonex, Extavia), glatiramer acetate (Copaxone), teriflunomide (Aubagio), and dimethyl fumarate (Tecfidera), collectively named BRACETD. Other treatments for multiple sclerosis (MS) have a narrower use, such as natalizumab (Tysabri) or fingolimod (Gilenya), among others.This study objective was to assess how well natalizumab and fingolimod helped treating MS (clinical effectiveness) and subsequently estimate what the cost of these treatments is in comparison to the benefit they bring to people with rapidly evolving severe MS that use them in the United Kingdom (UK) (cost-effectiveness).We used an international disease registry (MSBase), which collects clinical data from people with MS in various centers around the world to compare the effectiveness of natalizumab, fingolimod and BRACETD treatments. We used a technique called propensity score matching to obtain results from comparable patient groups. People treated with natalizumab had better disease control, namely with fewer relapses and higher improvement on their disability level, than patients on fingolimod or BRACETD. Conversely, there were no differences between each group of people on a measure called disability worsening.Based on these clinical results, we built an economic model that simulates the lifetime costs and consequences of treating people with MS with natalizumab in comparison with fingolimod. We found that using natalizumab was less costly and was more effective compared to using fingolimod in UK patients.

Antibody response against gastrointestinal antigens in demyelinating diseases of the central nervous system.

BACKGROUND: Antibodies against gastrointestinal antigens may indicate altered microbiota and immune responses in the gut. Recent experimental data suggest a connection between gastrointestinal immune responses and CNS autoimmunity. METHODS: Antibodies against gliadin, tissue transglutaminase (tTG), intrinsic factor (IF), parietal cells (PC) and Saccharomyces cerevisiae (ASCA) were screened in the sera of 45 patients with AQP4-seropositive neuromyelitis optica (NMO) and NMO spectrum diseases (NMO/NMO-SD), 17 patients with AQP4-seronegative NMO, 85 patients with clinically definite multiple sclerosis (MS), and 48 healthy controls (HC). RESULTS: Thirty-seven percentages of patients with AQP4-seropositive NMO/NMO-SD and 28% of patients with MS had at least one particular antibody in contrast to 8% of HC (P < 0.01, respectively). Antibodies were most common (46%) in AQP4-seropositive myelitis (P = 0.01 versus HS, P = 0.05 versus MS). Anti-gliadin and ASCA were more frequent in the AQP4-seropositive NMO-spectrum compared to controls (P = 0.01 and P < 0.05, respectively). CONCLUSION: Antibody responses against gastrointestinal antigens are common in MS and AQP4-seropositive NMO/NMO-SD, especially in longitudinally extensive myelitis.

Serum concentrations of 25-OH vitamin D in patients with systemic lupus erythematosus (SLE) are inversely related to disease activity: is it time to routinely supplement patients with SLE with vitamin D?

BACKGROUND: Low serum vitamin D concentrations have been reported in several autoimmune disorders. OBJECTIVE: To assess whether low serum vitamin D concentrations are related to disease activity of patients with systemic lupus erythematosus (SLE). METHODS: 378 patients from several European and Israeli cohorts were pooled and their disease activity was measured by two different methods: 278 patients had SLE disease activity-2000 (SLEDAI-2K) scores and 100 patients had European Consensus Lupus Activity Measurement (ECLAM) scores. In order to combine the two systems the scores were converted into standardised values (z-scores), enabling univariate summary statistics for the two variables (SLEDAI-2K and ECLAM). The commercial kit, LIAISON 25-OH vitamin D assay (310900-Diasorin) was used to measure serum concentration of 25-OH vitamin D in 378 patients with SLE. RESULTS: A significant negative correlation was demonstrated between the serum concentration of vitamin D and the standardised values (z-scores) of disease activity scores as measured by the SLEDAI-2K and ECLAM scales (Pearson's correlation coefficient r=-0.12, p=0.018). CONCLUSIONS: In a cohort of patients with SLE originating from Israel and Europe vitamin D serum concentrations were found to be inversely related to disease activity.

The Debrecen Stroke Database: demographic characteristics, risk factors, stroke severity and outcome in 8088 consecutive hospitalised patients with acute cerebrovascular disease.

BACKGROUND: High stroke mortality in central-eastern European countries might be due to higher stroke incidence, more severe strokes or less effective acute care than in countries with lower mortality rate. Hospital databases usually yield more detailed information on risk factors, stroke severity and short-term outcome than population-based registries. PATIENTS AND METHODS: The Debrecen Stroke Database, data of 8088 consecutively hospitalised patients with acute cerebrovascular disease in a single stroke centre in East Hungary between October 1994 and December 2006, is analysed. Risk factors were recorded and stroke severity on admission was scored by the Mathew stroke scale. The modified Glasgow outcome scale was used to describe patient condition at discharge. RESULTS: Mean age was 68+/-13 years, 11.4% had haemorrhagic stroke. The rate of hypertension on admission was 79% in men, and 84% in women, 40.3% of men and 19.8% of women were smokers, and 34% of all patients had a previous cerebrovascular disease in their history. Case fatality was 14.9%, and 43% had some disability at discharge. Outcome at discharge was worse with higher age, higher glucose, higher blood pressure, higher white cell count and erythrocyte sedimentation rate and more severe clinical signs on admission. In multivariate analysis admission blood pressure lost its significance in predicting outcome. CONCLUSIONS: In this large Hungarian stroke unit database hypertension on admission, smoking and previous cerebrovascular disease were more frequent than in most western databases. These findings indicate major opportunities for more efficient stroke prevention in this and probably other eastern European countries.

Genetically determined neuropathy (CMT 1A) accompanied by immune dysfunction: a case report.

Peripheral Myelin Protein 22 (PMP22) is mostly expressed in Schwann cells where it is essential in the compaction of myelin. The duplication of the PMP22 gene results in a hereditary demyelinating neuropathy of the Charcot-Marie-Tooth type 1A (CMT1A). So far there are only a few case reports suggesting that dysimmune mechanisms may take part in the pathophysiology of this disease. We describe three siblings carrying the duplication of the PMP22 gene, with a significant reduction of serum immunoglobulin G levels in all three cases and sural nerve vasculitis in the two women, which supports the proposition, that immune dysfunction may accompany this disease in some cases.

Epidemiology of familial multiple sclerosis in Hungary.

The prevalence of familial aggregation of multiple sclerosis (MS) is estimated between 5 and 10%. Studies emphasize the effect of genetic factors over the environment of the patients in the development of the disease. We investigated familial accumulation of MS in the cases of 1500 patients in five Hungarian MS centers. According to our data, the risk of familial MS in Hungary is lower than in other countries for which literature data are accessible. The literature does not contain any data for the prevalence of familial MS in Hungary and middle-eastern Europe.

Abnormal cell-specific expressions of certain protein kinase C isoenzymes in peripheral mononuclear cells of patients with systemic lupus erythematosus: effect of corticosteroid application.

We have studied the expressions of various protein kinase C (PKC) isoenzymes in T cells and monocytes from patients with systemic lupus erythematosus (SLE), in comparison to those of healthy controls and patients with other immunological disorders. As measured by Western blotting, the levels of PKCbeta, delta, eta, epsilon, theta and zeta (but not of PKCalpha) significantly decreased in T cells of SLE patients. In monocytes, however, we observed marked suppressions only in the expressions of PKCdelta, epsilon and zeta but not in the expressions of other PKC isoforms. In vivo corticosteroid application, as well as in vitro steroid treatment of monocytes, elevated the expressions of most isoforms close to normal values; however, the decreased levels of PKCtheta and zeta were not affected by steroid application. These alterations were characteristic to SLE because we could not detect any changes in the PKC levels in mononuclear cells of primary Sjögren's syndrome and mixed connective tissue disease patients. These results suggest that impaired PKC isoenzyme pattern may exist in the T cells and monocytes of SLE patients. Furthermore, the clinically efficient glucocorticoid application in SLE can increase the expression of some members of PKC system.

Natural coagulation inhibitor proteins in young patients with cerebral ischemia.

Disturbances of coagulation and fibrinolytic pathways were studied in 53 young patients with cerebral ischemia. Upon admission 26 of 53 patients had abnormality in at least one of the antithrombin-III, protein C, protein S activities or in activated protein C (APC) ratios. Three months after the first examination the majority of the previously detected abnormalities returned to normal values and the most frequent alterations were decrease in protein S activity (3 patients) and APC resistance (3 patients). Conditions resulting in impaired fibrinolysis were frequently detected upon admission. Elevation of plasminogen activator inhibitor-1, lipoprotein (a), and alpha-2-antiplasmin was present in 23, 10, and 4 cases, respectively. It is concluded that abnormalities of coagulation as well as of the fibrinolytic systems are prevalent in the acute phase of cerebral ischemia, however, the results may be significantly influenced by the disease process or the acute phase effect.

Basic characteristics of hospital stroke services in Eastern Hungary.

Stroke mortality is extremely high in Central-Eastern European countries. We report basic characteristics of a stroke unit in Eastern Hungary, including age and sex distribution; the proportion of transient ischemic attacks (TIA), ischemic and hemorrhagic strokes; case fatality; application of diagnostic methods; and length of stay for all patients treated with acute cerebrovascular disease over a 12-month period. Records of all patients with acute cerebrovascular disease (n = 522) discharged in 1995 from a stroke unit with a well defined catchment area of 220,000 inhabitants in Eastern Hungary were retrospectively analyzed. Case fatality was 18.6% for all patients and 21.1% after excluding cases with TIA. Computer tomography, duplex carotid ultrasound, cerebrospinal fluid examination and electroencephalography were performed in 79%, 77%, 7% and 2% of the patients, respectively. The database of the university hospital with the same catchment area was electronically searched for patients who were discharged with the diagnosis of stroke from the three departments of internal medicine. Stroke mortality data of the catchment area based on death certificates was obtained from the Central Statistical Bureau. Two hundred twenty-eight stroke deaths were reported in the catchment area in 1995. In the same period 97 stroke deaths occurred at the stroke unit and 76 at the departments of internal medicine. If we aim to treat all patients with acute stroke at the stroke unit, with the present stroke incidence and duration of hospital stay the current capacity of the stroke unit (1 bed per 10.000 inhabitants) should be doubled.

[Hemostatic abnormalities in ischemic stroke]. / Haemostasis eltérések ischaemiás stroke-ban.

The authors studied whether haemostatic abnormalities connected with the development of cerebral circulatory disturbances can be demonstrated in young stroke patients in whom Doppler and angiographic examination failed to reveal deviations indicative of stroke. They determined the in vivo activation of the coagulation system (TAT, F 1 + 2), the degree of secondary fibrinolysis (D-dimer), the plasma levels of the markers of fibrinolysis, with special regard to inhibitors: plasminogen activator inhibitor (PAI-1), alpha 2 antiplasmin (alpha 2 AP), alpha 2 macroglobulin (alpha 2 M), the frequency of pathologic serum lipoprotein (a)-Lp(a)-values and the association of PAI-1 and Lp(a) with the fibrinolytic system. They conclude that in the acute phase of the disease, the TAT and F 1 + 2 values were significantly elevated compared to the control, without change in the D-dimer value. The results suggest that in the tested period increased thrombin generation dominated and it significantly surpassed plasmin activity since the D-dimer values of that period did not indicate substantial increase in secondary fibrinolysis. The results of the study were separately analyzed in acute, chronic TIA and stroke groups. In the TIA and acute group the F 1 + 2 values, while in stroke the TAT values were more elevated. The in vitro fibrinolytic capacity of the patients significantly decreased compared to controls, showing significant correlation with the Lp(a) level, but not with the PAI value. Examination of the marker molecules renders possible to assess the degree of hypercoaguability and of endogenous lysis. Their knowledge is held important for judging the progression of the disease and the therapeutic consequences.

[Cerebral positron emission tomographic study in systemic lupus erythematosus]. / Agyi pozitron emissziós tomográfiai vizsgálatok systemás lupus erythematosusban.

The cerebral glucose metabolism in eight patients with systemic lupus erythematosus (SLE) and in five healthy controls were examined by positron emission tomography (PET) using 18-F-labeled deoxy-glucose (FDG) as tracer. One of the eight patients had no abnormality by magnetic resonance imaging (MRI), three of them had cerebral atrophy and four patients had multiple white matter hyperintensities and vascular infarcts in the striatum as assessed by MRI. With FDG-PET, inhomogeneous multifocal cerebral glucose hypometabolism was detected, more frequently in the temporal lobe of right hemisphere. The PET findings did not correlate always with the neurological symptoms. Abnormalities in brain metabolism can be detected more frequently by PET, than morphological changes by MRI, indicating the involvement of the central nervous system.

[First Hungarian experiences with positron emission tomography (PET) studies. Members of the PET working group]. / Elsö hazai tapasztalatok pozitron emissziós tomográfiás (PET) vizsgálatokkal. PET munkacsoport tagjai.

Diagnostic investigations commenced on the 28th of June 1994 in Hungary's and Central Europe's first PET Centre at the University Medical School of Debrecen. The Centre is equipped with a GE 4096 Plus whole body PET scanner. A metabolic tracer, 18F-deoxy-D-glucose (FDG), was used in the investigations. During the first 15 months 249 PET investigations were made in the Centre of which 242 were diagnostic and 7 normal subjects served as control for the patient studies with brain scans. The number of oncological indications (intra- and extracranial tumours, Hodgkin's lymphomas) was n = 105 (43.4% of the 242 diagnostic examinations), neurological investigations (without intracranial tumours) formed the dominant group (n = 117; 48.3%), whereas the number of cardiological indications was 20 (8.3%). The oncological studies included those of intracranial tumours (n = 76; 31.4%); thyroid tumours (n = 9; 3.7%); Hodgkin's lymphomas (n = 7; 2.9%) and other extracranial tumours (n = 13; 5.4%). The distribution of different neurological and psychiatric investigations was as follows: localization of focal epileptogen zone (n = 60; 24.8%); differential diagnosis of dementias (n = 30; 12.4%); exploration of cerebrovascular diseases (n = 10; 4.1%); and other neurological diseases (n = 17; 7.0%). The main objective of the cardiological PET investigations was the exploration of viable myocardium. The present paper overviews both the procedures (including administrative issues, as well) and the results of the first 249 FDG-PET investigations.

[Ischemic cerebrovascular lesion caused by left atrial myxoma]. / Bal pitvari myxoma átal okozott ischaemiás cerebrovascularis laesio.

A case presentation is given of a 40 years old woman with acute ischemic cerebrovascular lesion in the territory of the left middle cerebral artery caused by embolization from a myxoma in the left atrium. The tumor was diagnosed by transthoracic echocardiography. Histological examination after cardiac surgery revealed a benignant myxoma. In the six-month-long postoperative follow up gradual improvement of the neurological signs was observed. The most important morphological and clinical characteristics of myxomas are summarized. The necessity of detailed cardiological examination of each young patient with stroke is emphasized.

Sequence specificity of mRNA N6-adenosine methyltransferase.

The sequence specificity of chicken mRNA N6-adenosine methyltransferase has been investigated in vivo. Localization of six new N6-methyladenosine sites on Rous sarcoma virus (RSV) virion RNA has confirmed our extended consensus sequence for methylation: RGACU, where R is usually a G (7/12). We have also observed A (2/12) and U (3/12) at the -2 position (relative to m6A at +1) but never a C. At the +3 position, the U was observed 10/12 times; an A and a C were observed once each in weakly methylated sequences. The extent of methylation varied between the different sites up to a maximum of about 90%. To test the significance of this consensus sequence, it was altered by site-specific mutagenesis, and methylation was assayed after transfection of mutated RSV DNA into chicken embryo fibroblasts. We found that changing the G at -1 or the U at +3 to any other residue inhibited methylation. However, inhibition of methylation at all four of the major sites in the RSV src gene did not detectably alter the steady-state levels of the three viral RNA species or viral infectivity. Additional mutants that inactivated the src protein kinase activity produced less virus and exhibited relatively less src mRNA in infected cells.

[Significance of computer analysis of dynamic brain scintigraphy in patients with cerebrovascular disorders]. / Dinamikus agyszcintigráfiás vizsgálatok számítógépes elemzésének jelentösége cerebrovascularis betegek vizsgálatában.

Dynamic cerebral scintigraphy was performed on 41 patients with cerebrovascular disease. The diagnostic value of parametric images formed by a computer was correlated to angiographic findings and clinical sings, respectively. Having the appropriate software these examinations can be performed with traditional gamma-cameras. Analysis of parametric pictures increases the reliability of the method. Analysis of cinematic display of serial images had the highest sensitivity and accuracy, while time-of-maximum pictures had the highest specificity. In departments, where digitized subtraction angiography, single photon emission computed tomography or positron emission tomography is not available, the non invasive dynamic brain scintigraphy is a useful screening method, its application is proposed by the authors.